Multi-organ Autoimmune Disease Research Articles

Mortality in systemic sclerosis

Systemic sclerosis (SSc) has a case-based mortality that is one of the highest among the rheumatic diseases. This article is an appraisal of current knowledge regarding survival, causes of death and risk factors for reduced life-expectancy in systemic sclerosis (SSc). Recent systematic reviews of cohorts studies published worldwide have revealed a pooled standardized mortality ratio in SSc of 3.5, and reiterated the importance of heart-lung involvement as a major cause of death in this disease. Indeed, the pooled hazard ratio (HR) of mortality in SSc patients with pulmonary arterial hypertension (PAH) compared with those without is 3.5, while the pooled HR for mortality in those with interstitial lung disease is 2.6. The average life expectancy of patients with SSc is 16-34 years less than age-matched and sex-matched population peers. Current research efforts are focused on quantifying early as well as late mortality, and modeling for predictors of death in SSc, with the ultimate goal of attenuating this risk and improving survival, as new therapies emerge. Studies have consistently shown a substantially increased mortality in SSc, predominantly due to cardio-pulmonary complications. A better understanding of risk factors for mortality holds the promise of improving outcomes in this devastating multiorgan autoimmune disease.

AB0063 Gammadelta t cells and their intracellular cytokine profile in peripheral blood of patients with systemic lupus erythematosus

BackgroundGammadelta T cells represent a minor population of human peripheral blood T lymphocytes. As very rapid cytokine-producing cells, gammadelta T cells can regulate other lymphocytes activation and assist their local...

PD-1 controls effectors but not the generation or function of natural or induced regulatory T-cells (P1011)

Abstract During T cell activation, the balance of co-stimulatory and co-inhibitory interactions plays an important role in shaping the resulting T cell response. Co-inhibitory signals help maintain peripheral immune tolerance, and thus animals with defective co-inhibitory molecules, such as PD-1 KO mice, are predisposed to autoimmunity. Unlike PD-1 KO mice, which develop mild autoimmunity, adult Rag KO recipients of PD-1 KO hematopoietic stem cells (HSC) succumb to rapid and severe multi-organ autoimmune disease soon after T cells first emerge from the thymus, implicating PD-1 as a critical factor in the control of T cell self-reactivity during lymphopenia induced homeostatic proliferation (LIP). While we have found no reduction in the absolute number of FoxP3+ regulatory T cells (Treg) in diseased PD-1 KO vs. wild type (WT) HSC recipients, some studies have indirectly suggested that PD-1 deficiency may inhibit the development of induced Treg (iTreg) cells from conventional T cells in the periphery. We therefore investigated whether PD-1 deficiency results in an intrinsic inability of T cells to convert to iTreg in vivo, which could lead to disease in PD-1 KO HSC recipients. Surprisingly, our findings suggest that PD-1 deficiency does not inhibit the development of iTreg nor does it affect Treg suppressive function, and that in the context of LIP, co-inhibitor deficient effector T cells cause disease primarily by expanding beyond the ability of Treg to control them.

T-Cell Reconstitution after Thymus Xenotransplantation Induces Hair Depigmentation and Loss

Here we present a mouse model for T-cell targeting of hair follicles, linking the pathogenesis of alopecia to that of depigmentation disorders. Clinically, thymus transplantation has been successfully used to treat T-cell immunodeficiency in congenital athymia, but is associated with autoimmunity. We established a mouse model of thymus transplantation by subcutaneously implanting human thymus tissue into athymic C57BL/6 nude mice. These xenografts supported mouse T-cell development. Surprisingly, we did not detect multiorgan autoimmune disease. However, in all transplanted mice, we noted a striking depigmentation and loss of hair follicles. Transfer of T cells from transplanted nudes to syngeneic black-coated RAG−/− recipients caused progressive, persistent coat-hair whitening, which preceded patchy hair loss in depigmented areas. Further transfer experiments revealed that these phenomena could be induced by CD4+ T cells alone. Immunofluorescent analysis suggested that Trp2+ melanocyte-lineage cells were decreased in depigmented hair follicles, and pathogenic T cells upregulated activation markers when exposed to C57BL/6 melanocytes in vitro, suggesting that these T cells are not tolerant to self-melanocyte antigens. Our data raise interesting questions about the mechanisms underlying tissue-specific tolerance to skin antigens.

Proapoptotic Bak and Bax guard against fatal systemic and organ-specific autoimmune disease

Dysregulation of the "intrinsic" apoptotic pathway is associated with the development of cancer and autoimmune disease. Bak and Bax are two proapoptotic members of the Bcl-2 protein family with overlapping, essential roles in the intrinsic apoptotic pathway. Their activity is critical for the control of cell survival during lymphocyte development and homeostasis, best demonstrated by defects in thymic T-cell differentiation and peripheral lymphoid homeostasis caused by their combined loss. Because most bak(-/-)bax(-/-) mice die perinatally, the roles of Bax and Bak in immunological tolerance and prevention of autoimmune disease remain unclear. We show that mice reconstituted with a Bak/Bax doubly deficient hematopoietic compartment develop a fatal systemic lupus erythematosus-like autoimmune disease characterized by hypergammaglobulinemia, autoantibodies, lymphadenopathy, glomerulonephritis, and vasculitis. Importantly, these mice also develop a multiorgan autoimmune disease with autoantibodies against most solid glandular structures and evidence of glandular atrophy and necrotizing vasculitis. Interestingly, similar albeit less severe pathology was observed in mice containing a hematopoietic compartment deficient for only Bak, a phenotype reminiscent of the disease seen in patients with point mutations in BAK. These studies demonstrate a critical role for Bak and an ancillary role for Bax in safeguarding immunological tolerance and prevention of autoimmune disease. This suggests that direct activators of the intrinsic apoptotic pathway, such as BH3 mimetics, may be useful for treatment of diverse autoimmune diseases.

Identification of a lupus-susceptibility locus leading to impaired clearance of apoptotic debris on New Zealand Black chromosome 13

Systemic lupus erythematosus is a chronic multi-organ autoimmune disease marked mainly by the production of anti-nuclear antibodies. Nuclear antigens become accessible to the immune system following apoptosis and defective clearance of apoptotic debris has been shown in several knockout mouse models to promote lupus. However, genetic loci associated with defective clearance are not well defined in spontaneously arising lupus models. We previously showed that introgression of the chromosome 13 interval from lupus-prone New Zealand Black (NZB) mice onto a non-autoimmune B6 genetic background (B6.NZBc13) recapitulated many of the NZB autoimmune phenotypes. Here, we show that B6.NZBc13 mice have impaired clearance of apoptotic debris by peritoneal and tingible-body macrophages and have narrowed down the chromosomal interval of this defect using subcongenic mice with truncated NZB chromosome 13 intervals. This chromosomal region (81–94 Mb) is sufficient to produce polyclonal B and T cell activation, and expansion of dendritic cells. To fully recapitulate the autoimmune phenotypes seen in B6.NZBc13 mice, at least one additional locus located in the centromeric portion of the interval is required. Thus, we have identified a novel lupus susceptibility locus on NZB chromosome 13 that is associated with impaired clearance of apoptotic debris.

Accelerated atherosclerosis in systemic lupus erythematosus: mechanisms and prevention approaches

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by increased serum autoantibody levels and tissue damage. With improved diagnosis and more effective treatment of the resultant kidney disease, accelerated atherosclerosis has become a major cause of morbidity in patients suffering from SLE. Although the exact mechanisms for SLE-accelerated atherosclerosis are unknown, multiple factors have been established as potential players in this process. Among these potential players are dysregulation of T and B cell populations and increased circulating levels of inflammatory cytokines. In addition, SLE patients exhibit a proatherogenic lipid profile characterized by low HDL and high LDL and triglycerides. Recent therapeutic approaches have focused on targeting B cells, the producers of autoantibodies, but most studies do not consider the effects of these treatments on atherosclerosis. Evidence suggests that T cells play a major role in SLE-accelerated atherosclerosis. Therefore, therapies targeted at T cells may also prove invaluable in treating SLE and atherosclerosis.

Obstetric Nephrology

SLE is a multi-organ autoimmune disease that affects women of childbearing age. Renal involvement in the form of either active lupus nephritis (LN) at the time of conception, or a LN new onset or flare during pregnancy increases the risks of preterm delivery, pre-eclampsia, maternal mortality, fetal/neonatal demise, and intrauterine growth restriction. Consequently, current recommendations advise that the affected woman achieve a stable remission of her renal disease for at least 6 months before conception. Hormonal and immune system changes in pregnancy may affect disease activity and progression, and published evidence suggests that there is an increased risk for a LN flare during pregnancy. The major goal of immunosuppressive therapy in pregnancy is control of disease activity with medications that are relatively safe for a growing fetus. Therefore, the use of mycophenolate mofetil, due to increasing evidence supporting its teratogenicity, is contraindicated during pregnancy. Worsening proteinuria, which commonly occurs in proteinuric renal diseases toward the end of pregnancy, should be differentiated from a LN flare and/or pre-eclampsia, a pregnancy-specific condition clinically characterized by hypertension and proteinuria. These considerations present challenges that underscore the importance of a multidisciplinary team approach when caring for these patients, including a nephrologist, rheumatologist, and obstetrician who have experience with these pregnancy-related complications. This review discusses the pathogenesis, maternal and fetal risks, and management pertinent to SLE patients with new onset or a history of LN predating pregnancy.

Autoimmune Regulator (AIRE) Deficiency Is Associated with Embryonic loss and Generation of Autoantibodies Against the Uterus, Placenta, and Embryo.

The autoimmune regulator (AIRE) orchestrates T cell tolerance to both ubiquitous and tissue-restricted antigens. A deficiency in this gene in both humans and mice prevents the deletion of autoreactive thymocytes and causes multiorgan autoimmune disease and associated lymphocyte infiltration and autoantibody production. Additionally, mutations in AIRE result in infertility. While ovarian autoimmunity becomes prominent as Aire-deficient mice age, infertility is apparent in these mice prior to depletion of ovarian reserves. We investigated the cause of female infertility in six week old Aire–deficient (KO) mice possessing normal ovarian reserves by mating them to wild type (WT) males and assessing their pregnancy rate, pregnancy associated weight gain and serum progesterone at gestational day (GD) 5.5, 7.5 and 10.5. Fertility between Aire-KO (n=14) and WT (n=7) controls was comparable at ED5.5. However, pregnancy rates began to diverge at GD7.5, when 54% of Aire-KO (n=13) females were pregnant compared to 83% of WT mice (n=12). This trend became statistically significant at GD10.5, when 50% of Aire-KO females (n=18) were pregnant compared to 92% of WT (n=13) mice (P<0.05). The timing of infertility was reflected in gestation-associated weight gain: non-pregnant Aire-KO females gained weight through GD6.5, thereafter becoming reduced as compared to gravid animals (P<0.05). Serum progesterone was equivalent at GD5.5 in both genotypes regardless of fertility status, but was reduced 6-fold in non-pregnant WT and KO mice at GD10.5 (p=0.012) compared to pregnant controls. We next analyzed unique IgG autoantibody production against female reproductive tissues in virgin WT and Aire-KO females at 8, 12, 16 and 20 weeks of age as well as in 8 week old gravid WT and Aire-KO mice by western blot. To this end, the serum of WT and Aire-KO mice was used to probe uterine, placental and embryonic tissue lysates by western blot analysis. While uterine autoantibodies in were absent in virgin Aire-KO females at both 8 (n=5) and 12 (n=5) weeks of age, they were apparent in more than 60% of virgin females at 16 and 20 weeks of age (n=6 and 5, respectively). Additionally, uterine autoantibodies were detected in 25% of 8 week old gravid females (n=24). Similarly, anti-placenta autoantibodies were not identified in WT mice of any age; however, autoantibodies became apparent in some mice as age progressed. Finally, anti-embryo antibodies, while absent in WT mice, were found in 20–30% of 8 week old mice, and 100% of 20 week old virgin Aire-KO mice. These data suggest that peri-implantation embryonic loss occurs in young Aire-deficient females, independently of ovarian autoimmune disease. Although some infertility may be due to generation of autoantibodies against the reproductive tract and embryo, most animals did not exhibit autoantibody production until later in life. Thus, infertility in ovary-sufficient Aire-KO mice may be due to poor quality embryos, immune targeting of the female reproductive tract and/or embryo, or a failure of the uterine decidual response in the mother. Supported by NIHR21HD062879.

Type‐1 immunity drives early lethality in scurfy mice

Foxp3(+) regulatory T (Treg) cells modulate the functions of multiple immune cell types, and loss of Treg cells causes lethal, CD4(+) T-cell-dependent multiorgan autoimmune disease in both mice and humans. However, how different effector T-cell subets contribute to the severe autoimmunity observed in the absence of Treg cells remains controversial. We found that although expanded populations of Th1, Th2, and Th17 cells can be detected in scurfy (sf) mice, Th1 cells predominate. Moreover, using a genetic approach, we found that sf mice with deficiencies in type-1 immunity (sf × Ifngr1(-/-), sf × Tbx21(-/-), and sf × Ifngr1(-/-)/Tbx21(-/-)) have an extended lifespan that is associated with altered cytokine production and attenuated cutaneous and hepatic inflammation. By contrast, sf mice deficient in type-2 immune responses (sf × Stat6(-/-)) display a significantly reduced lifespan with increased hepatic inflammation, but decreased dermatitis. These data indicate that Th1 cells and their associated cytokines drive early immunopathology in Foxp3-deficient sf mice, highlighting the essential role of Treg cells in restraining Th1-cell-mediated autoimmunity.

Human Stromal (Mesenchymal) Stem Cells: Basic Biology and Current Clinical Use for Tissue Regeneration

Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number of clinical applications, e.g., non-healing bone fractures and defects and also non-skeletal degenerative diseases like heart failure. Currently, the numbers of clinical trials that employ MSC are increasing. However, several biological and biotechnological challenges need to be overcome to benefit from the full potential of hMSC. In this current review, we present some of the most important and recent advances in understanding of the biology of hMSC and their current and potential use in therapy.

Cutaneous Manifestations of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease of unknown etiology with many clinical manifestations. The skin is one of the target organs most variably affected by the disease. The American College of Rheumatology (ACR) established 11 criteria as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individuals and do not do well in that capacity. Cutaneous lesions account for four of these 11 revised criteria of SLE. Skin lesions in patients with lupus may be specific or nonspecific. This paper covers the SLE-specific cutaneous changes: malar rash, discoid rash, photosensitivity, and oral mucosal lesions as well as SLE nonspecific skin manifestations, their pathophysiology, and management. A deeper thorough understanding of the cutaneous manifestations of SLE is essential for diagnosis, prognosis, and efficient management. Thus, dermatologists should cooperate with other specialties to provide optimal care of SLE patient.

Absence of β2 Integrins Impairs Regulatory T Cells and Exacerbates CD4+ T Cell-Dependent Autoimmune Carditis

The immunopathogenic mechanisms mediating inflammation in multiorgan autoimmune diseases may vary between the different target tissues. We used the K/BxN TCR transgenic mouse model to investigate the contribution of CD4(+) T cells and β(2) integrins in the pathogenesis of autoimmune arthritis and endocarditis. Depletion of CD4(+) T cells following the onset of arthritis specifically prevented the development of cardiac valve inflammation. Genetic absence of β(2) integrins had no effect on the severity of arthritis and unexpectedly increased the extent of cardiovascular pathology. The exaggerated cardiac phenotype of the β(2) integrin-deficient K/BxN mice was accompanied by immune hyperactivation and was linked to a defect in regulatory T cells. These findings are consistent with a model in which the development of arthritis in K/BxN mice relies primarily on autoantibodies, whereas endocarditis depends on an additional contribution of effector T cells. Furthermore, strategies targeting β(2) integrins for the treatment of systemic autoimmune conditions need to consider not only the role of these molecules in leukocyte recruitment to sites of inflammation, but also their impact on the regulation of immunological tolerance.

Antibody binding to neuronal surface in movement disorders associated with lupus and antiphospholipid antibodies

Systemic lupus erythematosus is a multi-organ autoimmune disorder associated with autoantibodies of complex diversity. Antiphospholipid antibodies (aPL), which are commonly associated with lupus, create a pro-thrombotic tendency, but are also associated with non-thrombotic neurological features. Movement disorders are rare neuropsychiatric complications of lupus and antiphospholipid syndrome, and autoimmune and thromboembolic disease mechanisms have been proposed. We describe the clinical features, investigation findings, treatment, and outcome of six paediatric participants with movement disorders associated with lupus and/or aPL (six females, median age 13 y, range 8-15). To examine the autoantibody hypothesis, we used a neuronal cell line with dopaminergic characteristics and measured serum antibody binding to neuronal cell-surface antigens using flow cytometry. For comparison with the six participants, we used serum from healthy individuals (n=12, six females, median age 11 y, range 9-13) and children with other neurological diseases (n=13, seven females, median age 7 y, range 2-15). Of the six participants, two had lupus only, two had lupus with aPL, and two had aPL only. The movement disorder was chorea in four and parkinsonism in two. All four participants with chorea had aPL and movement disorder relapses. The two participants with parkinsonism did not have aPL, but had a progressive course until rituximab or plasma exchange resulted in neuropsychiatric remission. All six participants demonstrated elevated serum antibody binding to neuronal cell-surface antigens compared with healthy individuals and those with other neurological diseases. This report supports the association of chorea with aPL, but suggests a different autoimmune mechanism operates in lupus parkinsonism. The presence of antibody binding to neuronal cell-surface antigens supports a possible direct action of autoantibodies on neurons in patients with movement disorders associated with lupus and aPL.

Aire mediates peptide epitope-specific thymic deletion of self reactive T cells to prevent autoimmune uveitis (148.3)

Abstract Aire is a transcription factor required for the expression of many tissue specific antigens in the thymus. In the absence of functional Aire protein, human patients and mice develop multi-organ autoimmune disease, including autoimmune uveitis, due to a defect in negative selection. The development of spontaneous uveitis in the Aire KO mouse model is dependent on the eye antigen, interphotoreceptor retinoid-binding antigen (IRBP), which has Aire-regulated expression the thymus. To study the mechanism by which Aire prevents IRBP-dependent autoimmune uveitis, two tetramer reagents were generated to measure the frequency and phenotype of IRBP specific CD4+ T cells in the polyclonal repertoire of WT and Aire KO mice. Analysis of the polyclonal T cell repertoire of WT and Aire KO mice showed that T cells specific for both IRBP tetramers proliferated in Aire KO mice when they developed uveitis. However, tetramer staining of thymocytes showed that only one of the two tetramer binding populations were deleted via an Aire-dependent mechanism. These studies demonstrate that two types of IRBP-specific T cells participate in spontaneous autoimmune uveitis in Aire KO mice, those that are deleted in an Aire-dependent manner and those that are not deleted by Aire.

Development of autoreactive CD8+ T cells in Aire-deficient mice (101.38)

Abstract Autoimmune regulator (Aire) regulates the transcription of a myriad of self antigens in the thymus, which is important for the process of central tolerance to eliminate autoreactive T cells and to prevent autoimmune pathology. Aire-deficient mice (aire-/-) have previously been shown to develop multi-organ autoimmune disorder. We were interested in investigating the role of Aire for autoreactive CD8+ T cells using aire-/-Ia-/- mice. We found that CD8+ T cells were increased in aire-/-Ia-/- mice as compare with their aire+/+ or heterozygous littermates. Furthermore, aire-/-Ia-/- mice showed significantly lower body weight as compared with their littermates. Immune infiltrates mainly composed of CD11c+ cells and CD8+ T cells were found in various tissues of aire-/-Ia-/- mice, especially in liver, lung, pancreas and stomach. Autoantibody was detected in the serum of aire-/-Ia-/- mice directed against gastric tissue and was determined to be predominantly IgM. Collectively, our study shows that autoreactive CD8+ T cells arise on the background of Aire-deficiency are capable of initiating and promoting autoimmunity in the absence of CD4+ T cells.

Increased IL‐17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model

Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal failure are hallmarks of the disease. The critical mechanisms causing chronic mucocutaneous candidiasis in APS-1 patients have not been identified although autoantibodies to cytokines are implicated in the pathogenesis. To investigate whether the Th reactivity to Candida albicans (C. albicans) and other stimuli was altered, we isolated PBMC from APS-1 patients and matched healthy controls. The Th17 pathway was upregulated in response to C. albicans in APS-1 patients, whereas the IL-22 secretion was reduced. Autoantibodies against IL-22, IL-17A and IL-17F were detected in sera from APS-1 patients by immunoprecipitation. In addition, Aire-deficient (Aire(0/0) ) mice were much more susceptible than Aire(+/+) mice to mucosal candidiasis and C. albicans-induced Th17- and Th1-cell responses were increased in Aire(0/0) mice. Thus an excessive IL-17A reactivity towards C. albicans was observed in APS-1 patients and Aire(0/0) mice.

The role of Aire in clonal selection

In his clonal selection theory, Frank Macfarlane Burnet predicted that autoreactive lymphocytes are deleted to prevent autoimmunity. This and other principles of lymphocyte behavior outlined by Burnet guided many studies that lead to our current understanding of thymic selection. Thus, when the genetic mutation responsible for autoimmune polyglandular syndrome type 1 was mapped to the autoimmune regulator (AIRE) gene, and Aire was found to be highly expressed in thymic epithelium, studying the role of Aire in negative selection made sense in the context of modern models of thymic selection. We now know Aire is a transcription factor required for the expression of many tissue-specific antigens (TSAs) in the thymus. In the absence of functional Aire, human patients and mice develop multi-organ autoimmune disease because of a defect in thymic negative selection. In addition to its role in the thymus, recent work in our lab suggests that extrathymic Aire-expressing cells have an important role in the clonal deletion of autoreactive CD8+ T cells. In this review, we summarize the latest studies on thymic and peripheral Aire-expressing cells, as well as other TSA-expressing stromal cell populations in peripheral lymphoid organs. We also discuss theoretical differences in thymic and peripheral Aire function that warrant further studies.

Transgenic overexpression of anti-double-stranded DNA autoantibody and activation of Toll-like receptor 4 in mice induce severe systemic lupus erythematosus syndromes

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characteristized by the presence of autoantibodies against double-stranded DNA (anti-dsDNA) in sera at high levels. Bacterial infections in SLE are associated with higher morbidity and mortality. Our goal was to observe the interaction between these 2 factors in the pathogenesis of lupus. We generated transgenic mice with monoclonal anti-dsDNA to investigate the development of lupus. By challenging the mice in vitro and in vivo with Toll-like receptor 4 (TLR4) ligand lipopolysaccharides (LPS), we were able to examine the role of bacterial infection in SLE. In our study, the transgenic mice with a secreted form of anti-dsDNA were found to have higher levels of anti-nuclear antibodies, anti-dsDNA, blood urea nitrogen, and proteinuria. The splenocytes of the mice stimulated with LPS secreted more anti-dsDNA, IFN-γ, and IL-10. After injecting them with LPS in vivo, we further found higher immune complex depositions and IL-10 in the kidneys of the transgenic mice. Moreover, the LPS-injected transgenic mice had higher mortality rate. This is the first transgenic model to demonstrate that only 2 risk factors, pathogenic anti-dsDNA and TLR4 activation, induce severe SLE syndromes in normal mice through the overproduction of IL-10 and IFN-γ. These findings imply that anti-dsDNA and bacterial infections have pivotal roles in the pathogenesis of SLE; the inhibition of TLR4 may be regarded as a therapeutic target.

Novel sequence variation of AIRE and detection of interferon‐ω antibodies in early infancy

Autoimmune polyendocrine syndrome type I (APS I) is a rare primary immunodeficiency disorder characterized by chronic mucocutaneous candidiasis, multi-organ autoimmunity and ectodermal dysplasia. Autoantibodies to parathyroid and adrenal glands and type I interferons (IFN) are hallmarks of APS I, which results from mutations in the autoimmune regulator (AIRE) gene. We wished to study clinical, immunological and genetic features of APS I in Hungarian patients, and to correlate anti-IFN-omega serum concentration with APS I and other multi-organ autoimmune diseases. Detailed analysis of patients with APS I and multi-organ autoimmune diseases. Seven patients with APS I and 11 patients with multi-organ autoimmune diseases were studied. Mutational analysis was performed by bidirectional sequencing of AIRE. Antibodies against IFN-omega and endocrine organ-specific autoantigens were studied with radioimmunoassay. RFLP was performed by digestion of DNA with Hin6I restriction enzyme. AIRE sequence analysis revealed homozygous c.769C>T mutations in three patients and compound heterozygous sequence variants (c.769C>T/c.44_66dup26bp; c.769C>T/c.965_977del13bp; c.769C>T/c.1344delC) in four patients with APS I. All the six live patients tested had markedly elevated IFN-omega antibodies, which were not found in heterozygous siblings or parents. One of the identified patients was negative for antibodies against IFN-omega at 6 weeks of age, but became positive at 7 months. At age 1, he is still without symptoms of the disease. In contrast to patients with APS I, no AIRE mutation or elevation of IFN-omega antibodies were detected in patients with multi-organ autoimmune diseases. This is the first overview of patients diagnosed with APS I in Hungary. A novel c.1344delC mutation in AIRE was detected. Anti-IFN-omega antibodies seem to appear very early in life and are helpful to differentiate APS I from other multi-organ autoimmune diseases.